Despite the identification of HIV-1 as the causative agent of the acquired immune deficiency syndrome (AIDS), definition of a protective immune response against the virus has remained an elusive goal. A vigorous cytotoxic lymphocyte (CTL) response to HIV-1 has been detected in infected individuals, and in vitro data indicate that lymphocytes from infected individuals of the CD8 phenotype can inhibit virus replication in vitro. Functional studies suggest that these cells are typical CTL, yet the relevant target antigens recognized have not been identified. Our laboratory has recently established a technique for the isolation and long-term propogation of HIV-1-specific CTL clones, and have mapped the actual CTL epitopes recognized by these cells using synthetic viral peptides. The purpose of this proposal is to examine the ability of CTL clones of defined epitope specificity to inhibit the replication of HIV-1 in order to determine the functional activity of these cells in vitro. Specifically, we propose to (1) examaine the ability of CTL clones to inhibit replication of HIV-1 in lymphocytes (2) examine the ability of CTL clones to inhibit HIV-1 replication in monocytes (3) determine the mechanisms of the CTL-induced inhibition of virus replication (4) determine the role of antigenic variation in escape from CTL recognition. These studies should both provide insight into the immunopathogenesis of HIV-1 infection, and are directly relevant to potential HIV-1 immunization and immunotherapy strategies.